Functional imaging reveals rapid reorganization of cortical activity after parietal inactivation in monkeys

Impairments of spatial awareness and decision making occur frequently as a consequence of parietal lesions. Here we used event-related functional MRI (fMRI) in monkeys to investigate rapid reorganization of spatial networks during reversible pharmacological inactivation of the lateral intraparietal area (LIP), which plays a role in the selection of eye movement targets. We measured fMRI activity in control and inactivation sessions while monkeys performed memory saccades to either instructed or autonomously chosen spatial locations. Inactivation caused a reduction of contralesional choices. Inactivation effects on fMRI activity were anatomically and functionally specific and mainly consisted of: (i) activity reduction in the upper bank of the superior temporal sulcus (temporal parietal occipital area) for single contralesional targets, especially in the inactivated hemisphere; and (ii) activity increase accompanying contralesional choices between bilateral targets in several frontal and parieto-temporal areas in both hemispheres. There was no overactivation for ipsilesional targets or choices in the intact hemisphere. Task-specific effects of LIP inactivation on blood oxygen level-dependent activity in the temporal parietal occipital area underline the importance of the superior temporal sulcus for spatial processing. Furthermore, our results agree only partially with the influential interhemispheric competition model of spatial neglect and suggest an additional component of interhemispheric cooperation in the compensation of neglect deficits

VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart

Peer reviewe

Revealing the complexity of meniscus microvasculature through 3D visualization and analysis

Three-dimensional information is essential for a proper understanding of the healing potential of the menisci and their overall role in the knee joint. However, to date, the study of meniscal vascularity has relied primarily on two-dimensional imaging techniques. Here we present a method to elucidate the intricate 3D meniscal vascular network, revealing its spatial arrangement, connectivity and density. A polymerizing contrast agent was injected into the femoral artery of human cadaver legs, and the meniscal microvasculature was examined using micro-computed tomography at different levels of detail and resolution. The 3D vascular network was quantitatively assessed in a zone-base analysis using parameters such as diameter, length, tortuosity, and branching patterns. The results of this study revealed distinct vascular patterns within the meniscus, with the highest vascular volume found in the outer perimeniscal zone. Variations in vascular parameters were found between the different circumferential and radial meniscal zones. Moreover, through state-of-the-art 3D visualization using micro-CT, this study highlighted the importance of spatial resolution in accurately characterizing the vascular network. These findings, both from this study and from future research using this technique, improve our understanding of microvascular distribution, which may lead to improved therapeutic strategies

α-Synuclein aggregation inhibitory activity of the bromotyrosine derivatives aerothionin and aerophobin-2 from the subtropical marine sponge Aplysinella sp

The neuronal protein α-synuclein (α-syn) is one of the main constituents of intracellular amyloid aggregations found in the post-mortem brains of Parkinson’s disease (PD) patients. Recently, we screened the MEOH extracts obtained from 300 sub-tropical marine invertebrates for α-syn binding activity using affinity MS and this resulted in the extract of the Verongida marine sponge Aplysinella sp. 1194, (QM G339263) displaying molecules that bind to the protein. The subsequent bioassay-guided separation of the Aplysinella sp. extract led to the isolation of the known bromotyrosine derivatives (+)-aerothionin (1) and (+)-aerophobin-2 (2). Both compounds bind to α-syn as detected by a MS affinity assay and inhibit α-syn aggregation in an assay that uses the fluorescence probe, thioflavin T, to detect aggregation. (+)-Aerothionin (1) was toxic to primary dopaminergic neurons at its expected α-syn aggregation inhibitory concentration and so could not be tested for pSyn aggregates in this functional assay. (+)-Aerophobin-2 (2) was not toxic and shown to weakly inhibit pSyn aggregation in primary dopaminergic neurons at 10 µM.Peer reviewe

Hesperine, a new imidazole alkaloid and α-synuclein binding activity of 1-methyl-1,2,7,8-tetrahydro-2,8-dioxoadenosine from the marine sponge Clathria (Thalysias) cf. hesperia

During a high-throughput screen of 300 Australian marine invertebrate extracts, the extract of the marine sponge Clathria (Thalysias) cf. hesperia was identified with α-synuclein binding activity. The bioassay-guided purification of this extract resulted in the isolation of 1-methyl-1,2,7,8-tetrahydro-2,8-dioxoadenosine (2) as the α-syn binder along with one new compound, hesperine (1), and five known compounds, indole-3-carboxaldehyde (3), (Z)-2'-demethylaplysinopsin (4), 2-amino-4'-hydroxyacetophenone (5), 4-hydroxybenzoic acid (6) and 4-hydroxybenzaldehyde (7). Herein, we report the structure elucidation of hesperine (1) and α-syn binding activity of 1-methyl-1,2,7,8-tetrahydro-2,8-dioxoadenosine (2).Peer reviewe

Adaptation of cortical activity to sustained pressure stimulation on the fingertip

Background Tactile adaptation is a phenomenon of the sensory system that results in temporal desensitization after an exposure to sustained or repetitive tactile stimuli. Previous studies reported psychophysical and physiological adaptation where perceived intensity and mechanoreceptive afferent signals exponentially decreased during tactile adaptation. Along with these studies, we hypothesized that somatosensory cortical activity in the human brain also exponentially decreased during tactile adaptation. The present neuroimaging study specifically investigated temporal changes in the human cortical responses to sustained pressure stimuli mediated by slow-adapting type I afferents. Methods We applied pressure stimulation for up to 15 s to the right index fingertip in 21 healthy participants and acquired functional magnetic resonance imaging (fMRI) data using a 3T MRI system. We analyzed cortical responses in terms of the degrees of cortical activation and inter-regional connectivity during sustained pressure stimulation. Results Our results revealed that the degrees of activation in the contralateral primary and secondary somatosensory cortices exponentially decreased over time and that intra- and inter-hemispheric inter-regional functional connectivity over the regions associated with tactile perception also linearly decreased or increased over time, during pressure stimulation. Conclusion These results indicate that cortical activity dynamically adapts to sustained pressure stimulation mediated by SA-I afferents, involving changes in the degrees of activation on the cortical regions for tactile perception as well as in inter-regional functional connectivity among them. We speculate that these adaptive cortical activity may represent an efficient cortical processing of tactile information.open

Anti-angiogenic therapy for cancer: Current progress, unresolved questions and future directions

Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies. © 2014 The Author(s)

Factors Affecting Frequency Discrimination of Vibrotactile Stimuli: Implications for Cortical Encoding

BACKGROUND: Measuring perceptual judgments about stimuli while manipulating their physical characteristics can uncover the neural algorithms underlying sensory processing. We carried out psychophysical experiments to examine how humans discriminate vibrotactile stimuli. METHODOLOGY/PRINCIPAL FINDINGS: Subjects compared the frequencies of two sinusoidal vibrations applied sequentially to one fingertip. Performance was reduced when (1) the root mean square velocity (or energy) of the vibrations was equated by adjusting their amplitudes, and (2) the vibrations were noisy (their temporal structure was irregular). These effects were super-additive when subjects compared noisy vibrations that had equal velocity, indicating that frequency judgments became more dependent on the vibrations' temporal structure when differential information about velocity was eliminated. To investigate which areas of the somatosensory system use information about velocity and temporal structure, we required subjects to compare vibrations applied sequentially to opposite hands. This paradigm exploits the fact that tactile input to neurons at early levels (e.g., the primary somatosensory cortex, SI) is largely confined to the contralateral side of the body, so these neurons are less able to contribute to vibration comparisons between hands. The subjects' performance was still sensitive to differences in vibration velocity, but became less sensitive to noise. CONCLUSIONS/SIGNIFICANCE: We conclude that vibration frequency is represented in different ways by different mechanisms distributed across multiple cortical regions. Which mechanisms support the “readout” of frequency varies according to the information present in the vibration. Overall, the present findings are consistent with a model in which information about vibration velocity is coded in regions beyond SI. While adaptive processes within SI also contribute to the representation of frequency, this adaptation is influenced by the temporal regularity of the vibration

PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF-induced endothelial proliferation

VEGF induces normal or aberrant angiogenesis depending on its dose in the microenvironment around each producing cell in vivo. This transition depends on the balance between VEGF-induced endothelial stimulation and PDGF-BB-mediated pericyte recruitment, and co-expression of PDGF-BB normalizes aberrant angiogenesis despite high VEGF doses. We recently found that VEGF over-expression induces angiogenesis in skeletal muscle through an initial circumferential vascular enlargement followed by longitudinal splitting, rather than sprouting. Here we investigated the cellular mechanism by which PDGF-BB co-expression normalizes VEGF-induced aberrant angiogenesis. Monoclonal populations of transduced myoblasts, expressing similarly high levels of VEGF alone or with PDGF-BB, were implanted in mouse skeletal muscles. PDGF-BB co-expression did not promote sprouting and angiogenesis that occurred through vascular enlargement and splitting. However, enlargements were significantly smaller in diameter, due to a significant reduction in endothelial proliferation, and retained pericytes, which were otherwise lost with high VEGF alone. A time-course of histological analyses and repetitive intravital imaging showed that PDGF-BB co-expression anticipated the initiation of vascular enlargement and markedly accelerated the splitting process. Interestingly, quantification during in vivo imaging suggested that a global reduction in shear stress favored the initiation of transluminal pillar formation during VEGF-induced splitting angiogenesis. Quantification of target gene expression showed that VEGF-R2 signaling output was significantly reduced by PDGF-BB co-expression compared to VEGF alone. In conclusion, PDGF-BB co-expression prevents VEGF-induced aberrant angiogenesis by modulating VEGF-R2 signaling and endothelial proliferation, thereby limiting the degree of circumferential enlargement and enabling efficient completion of vascular splitting into normal capillary networks despite high VEGF doses